Role of the Fanconi Anemia DNA Repair Pathway in Epidermal Stem and Progenitor Cells

项目概要/摘要：人类皮肤和粘膜主要由角质形成细胞组成， 在维持器官和生物体屏障免受环境侵害方面发挥关键作用。列入这 损伤是引起基因组不稳定性和DNA损伤的内源性和外源性DNA毒素。DNA修复 一旦发生DNA损伤，这种机制是一种关键的二级防御。虽然身体里的所有细胞 进化出复杂的机制来修复DNA损伤，缺陷修复的后果是不同的， 不同的器官，并可能植根于发育过程，仍然知之甚少。无处是 器官特异性DNA修复的重要性比遗传的人类基因组不稳定性更明显 范可尼贫血（FA），其中身体中的每个细胞都不能修复某些类型的DNA 正确的伤害。该疾病的一个普遍分子特征是缺乏FA DNA修复途径。 该疾病的临床特征包括先天性异常，骨髓衰竭，奇怪的是， 对角质形成细胞转化的易感性。FA患者表现出对鳞状细胞癌的极端易感性， 癌症（SCC）的皮肤和粘膜在生命的早期，我们最近发现了新的粘附缺陷 用电子显微镜研究正常的病人皮肤。FA通路在正常人中的作用 角质形成细胞和发育起源的缺陷组织稳态和SCC的易感性将是 在这里检查。基于初步数据，我推测FA通路的缺失会损害信号传导和屏障功能。 体细胞表皮干细胞和祖细胞（ESPCs）的功能，这些异常反过来又促进 皮肤的3D工程模型中的组织缺陷以及最终SCC易感性和进展。这些 将使用新的发育系统来测试假设，其中诱导的多能干细胞产生 来自FA患者的细胞被诱导性地补充以重建FA通路功能并分化为 角质形成细胞和3D表皮。项目的所有实验要素都已到位，我期待着一次学习 这将使我能够全面了解发展过程， 有缺陷的体细胞ESPCs和由此产生的遗传性疾病易感性作为坚实的学术生涯基础。

Project Summary/Abstract: Human skin and mucosa are composed predominantly of keratinocytes, which play a critical role in maintaining organ and organismal barriers against environmental insults. Included in such insults are endogenous and exogenous DNA toxins that cause genome instability and DNA damage. DNA repair mechanisms are a critical secondary defense once DNA damage has occurred. While all cells in the body have evolved sophisticated mechanisms to repair DNA damage, the consequences of defective repair are distinct for different organs and are likely rooted in developmental processes that remain poorly understood. Nowhere is the importance of organ-specific DNA repair more apparent than in the inherited human genome instability disorder Fanconi Anemia (FA), wherein every cell in the body is incapable of repairing certain types of DNA damage properly. A universal molecular feature of the disease is the absence of the FA DNA repair pathway. Clinical features of the disease include congenital abnormalities, bone marrow failure and, curiously, a unique susceptibility to keratinocyte transformation. FA patients exhibit an extreme susceptibility to squamous cell carcinomas (SCCs) of the skin and mucosa early in life, and we have recently uncovered novel adhesion defects in normal-appearing patient skin using electron microscopic studies. The role of the FA pathway in normal keratinocytes and developmental origins for defective tissue homeostasis and SCC predisposition will be examined here. I hypothesize, based on preliminary data, that FA pathway loss impairs signaling and barrier functions of somatic epidermal stem and progenitor cells (ESPCs) and that these abnormalities, in turn, promote tissue defects in 3D engineered models of skin as well as ultimately SCC susceptibility and progression. These hypotheses will be tested using a novel developmental system wherein induced pluripotent stem cells generated from FA patients are inducibly complemented to reconstitute FA pathway function and differentiated into keratinocytes and 3D epidermis. All experimental elements of the projects are in place and I anticipate a learning experience which will allow me to gain a comprehensive understanding of developmental processes leading to defective somatic ESPCs and resulting inherited disease susceptibilities as a solid academic career foundation.